The goal of this collaborative project among investigators led by Drs. Michael Boehnke at the University of Michigan, Steven McCarroll of Harvard University and the Broad Institute, and Carlos Pato at the University of Southern California, is to use high-throughput DNA sequencing to identify genes and pathways that contribute to the risk for schizophrenia and bipolar disorder, and to construct a data resource for future genetic studies of these and other psychiatric disorders. This proposal builds on active collaborations among our groups on these important disorders and more generally on our experience in building genome variation resources, such as the 1000 Genomes Project, that are used throughout human genetics. Our research team combines strengths in high-throughput genetics and genomics, development and application of innovative computational and statistical analyses that maximize the benefits of new technologies, and leadership of large scientific consortia. In four Specific Aims, we propose whole genome sequencing (at ~30x coverage) and statistical analysis of 10,000 well-phenotyped and re-contactable individuals from the Genomic Psychiatry Cohort (GPC), equally divided among schizophrenia cases, bipolar cases, and psychiatrically normal controls, and comprised of equal numbers of European-Ancestry (EA), African-Ancestry (AA), and Latino individuals. We will carry out association analysis comparing schizophrenia cases to controls, bipolar cases to controls, and the combined cases to controls in the resulting sequence data, and by collaboration and meta-analysis with other investigators with relevant sequence data that become available. We will also use these sequence data as part of a reference panel to impute into tens of thousands of other genomes in the broader Psychiatric GWAS Consortium (PGC) data to allow association analysis based on substantially larger numbers of individuals. Finally, we will share data and methods to support similar studies of other psychiatric phenotypes and more broadly across the scientific community. The successful completion of these aims will provide new insights into molecular etiology that could catalyze breakthroughs in the prevention, treatment, and diagnosis of schizophrenia and bipolar disorder.